CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS

铂类抗癌药物的化学和生物学

• 批准号: 7955152
• 负责人: Stephen J. Lippard
• 金额: $ 0.22万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955152
• 关键词: Antineoplastic Agents; Base Pairing; Biology; Chemistry; Cisplatin; Colorectal Cancer; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Adducts; DNA Structure; Data; Funding; Genetic Transcription; Grant; Institution; Left; Lesion; Major Groove; Modeling; Molecular Conformation; Molecular Mechanisms of Action; Mus; Platinum; Platinum Compounds; Proteins; Research; Research Personnel; Resources; Side; Site; Source; Structural Models; Structure-Activity Relationship; United States National Institutes of Health; Work; X ray diffraction analysis; X-Ray Diffraction; adduct; antitumor agent; crosslink; cytotoxicity; in vivo; interest; pyridine; repaired; structural biology; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The platinum compound cis-[Pt(NH3)2(pyridine)Cl]Cl has previously demonstrated potent cytotoxicity in a screen against in vivo murine tumor models. This result is of particular interest because this compound forms only monofunctional adducts with DNA, and thus does not follow the classic structure-activity relationship for platinum anti-tumor agents that requires two leaving groups to be present in a cis conformation. Recent data has shown this compound may be recognized by cellular repair proteins and block transcription in a manner that is unique to monofunctional platinum compounds, but similar to cisplatin and other bifunctional platinum compounds. It is therefore desirable to obtain a detailed structural model of this platinum-DNA adduct, which may help to explain the unexpected activity of the complex. We have recently crystallized a DNA dodecamer duplex containing a single {Pt(NH3)2(pyridine)}-dG adduct, and collected X-ray diffraction data to 2.17 ¿. The global structure of the DNA is quite different from that of DNA containing a platinum intrastrand d(GpG) cross-link. The latter platinated duplex is bent by ~40¿ towards the major groove at the site of the cross-link, yet the monofunctional platinumdG lesion causes no significant distortion of the double helix. Like the cisplatin intrastrand cross-link, however, the monofunctional adduct creates a distorted base pair step to the 5' side of the platinum site that may be correlated to antitumor activity. These data allow us to reevaluate the structure-activity relationship of platinum anticancer agents to include monofunctional, "non-classical" platinum compounds, and to use this evidence to work towards elucidating the molecular mechanism of action of a unique platinum complex that may be able to be used in treatment of colorectal cancer.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 铂化合物CIS- [PT（NH3）2（吡啶）Cl] Cl在反对体内鼠肿瘤模型的筛选中已经显示出潜在的细胞毒性。该结果特别令人感兴趣，因为该化合物仅形成具有DNA的单官能加合物，因此不遵循铂抗肿瘤剂的经典结构 - 活性关系，这些关系需要两个离开组以CIS构象中存在。最近的数据表明，该化合物可以通过细胞修复蛋白和以单官能铂化合物为特殊的方式来识别，但类似于顺铂和其他双功能铂金化合物。因此，希望获得该铂DNA加合物的详细结构模型，这可能有助于解释该复合物的意外活动。最近，我们结晶了一个含有单个{pt（nh3）2（pyridine）} - dg添加的DNA十二焦双链体，并将X射线衍射数据收集到2.17。 DNA的全局结构与含有铂静脉内D（GPG）交联的DNA的结构完全不同。后者的铂双链体弯曲〜40“朝着交叉链路部位的主要凹槽弯曲，但单功能铂DG病变不会引起双螺旋的显着变形。但是，像顺铂内链交联一样，单官能添加会产生扭曲的基对台阶到铂部位的5'侧，可能与抗肿瘤活性相关。这些数据使我们能够重新评估铂抗癌剂的结构活性关系，包括单功能，“非经典”铂化合物，并使用该证据来阐明可以用于治疗结婚癌症的独特铂综合体的分子机制。